Predicting the daily gastrointestinal doses of stereotactic body radiation therapy for pancreatic cancer based on the shortest distance between the tumor and the gastrointestinal tract using daily computed tomography images

Objectives: We aimed to investigate whether daily computed tomography (CT) images could predict the daily gastroduodenal, small intestine, and large intestine doses of stereotactic body radiation therapy (SBRT) for pancreatic cancer based on the shortest distance between the gross tumor volume (GTV) and gastrointestinal (GI) tract. Methods: Twelve patients with pancreatic cancer received SBRT of 40 Gy in five fractions. We recalculated the reference clinical SBRT plan (PLANref) using daily CT images and calculated the shortest distance from the GTV to each GI tract. The maximum dose delivered to 0.5 cc (D0.5cc) was evaluated for each planning at-risk volume of the GI tract. Spearman’s correlation test was used to determine the association between the daily change in the shortest distance (Δshortest distance) and the ratio of ΔD0.5cc dose to D0.5cc dose in PLANref (ΔD0.5cc/PLANref) for quantitative analysis. Results: The median shortest distance in PLANref was 0 mm in the gastroduodenum (interquartile range, 0–2.7), 16.7 mm in the small intestine (10.0–23.7), and 16.7 mm in the large intestine (8.3–28.1 mm). The D0.5cc of PLANref in the gastroduodenum was >30 Gy in all patients, with 10 (83.3%) having the highest dose. A significant association was found between the Δshortest distance and ΔD0.5cc/ PLANref in the small or large intestine (p < 0.001) but not in the gastroduodenum (p = 0.404). Conclusions: The gastroduodenum had a higher D0.5cc and predicting the daily dose was difficult. Daily dose calculations of the GI tract are recommended for safe SBRT. Advances in knowledge: This study aimed to predict the daily doses in SBRT for pancreatic cancer from the shortest distance between the GTV and the gastrointestinal tract. Daily changes in the shortest distance can predict the daily dose to the small or large intestines, but not to the gastroduodenum.


INTRODUCTION
2][3] The advantages of SBRT include delivery of higher doses to the tumor and a shorter treatment period, which shortens the interruption of intense systemic chemotherapy.However, higher radiation dose delivery to the target lesion is often limited by the proximity of radiosensitive gastrointestinal (GI) organs.Moreover, inter-or intrafractional Objectives: We aimed to investigate whether daily computed tomography (CT) images could predict the daily gastroduodenal, small intestine, and large intestine doses of stereotactic body radiation therapy (SBRT) for pancreatic cancer based on the shortest distance between the gross tumor volume (GTV) and gastrointestinal (GI) tract.Methods: Twelve patients with pancreatic cancer received SBRT of 40 Gy in five fractions.We recalculated the reference clinical SBRT plan (PLAN ref ) using daily CT images and calculated the shortest distance from the GTV to each GI tract.The maximum dose delivered to 0.5 cc (D 0.5cc ) was evaluated for each planning at-risk volume of the GI tract.Spearman's correlation test was used to determine the association between the daily change in the shortest distance (Δshortest distance) and the ratio of ΔD 0.5cc dose to D 0.5cc dose in PLAN ref (ΔD 0.5cc /PLAN ref ) for quantitative analysis.Results: The median shortest distance in PLAN ref was 0 mm in the gastroduodenum (interquartile range, 0-2.7), 16.7 mm in the small intestine (10.0-23.7),and 16.7 mm in the large intestine (8.3-28.1 mm).The D 0.5cc of PLAN ref in the gastroduodenum was >30 Gy in all patients, with 10 (83.3%) having the highest dose.A significant association was found between the Δshortest distance and ΔD 0.5cc / PLAN ref in the small or large intestine (p < 0.001) but not in the gastroduodenum (p = 0.404).Conclusions: The gastroduodenum had a higher D 0.5cc and predicting the daily dose was difficult.Daily dose calculations of the GI tract are recommended for safe SBRT.

Advances in knowledge:
This study aimed to predict the daily doses in SBRT for pancreatic cancer from the shortest distance between the GTV and the gastrointestinal tract.Daily changes in the shortest distance can predict the daily dose to the small or large intestines, but not to the gastroduodenum.

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8][9] Therefore, daily dose evaluation is essential to ensure the safe delivery of SBRT.
Online adaptive radiotherapy has been used to address these challenges, and several therapeutic outcomes assessed using magnetic resonance-guided linear accelerators (MR-LINAC) or artificial intelligence-driven systems, such as ETHOS (Varian Medical Systems, Palo Alto, CA), have been reported in patients with pancreatic cancer. 10,11However, the availability of adaptive therapy is limited as it requires specialized equipment and qualified healthcare professionals (such as medical physicists or physicians).Moreover, dose uncertainties due to intrafractional motion may occur as the image acquisition to beam-on process may take several tens of minutes when using MR-LINAC or ETHOS. 10,12ong the online adaptive workflow steps before beam delivery, contouring is the most time-consuming step. 13,14However, daily plan adaptation is no longer necessary in >40% of total fractions. 14Therefore, it may be useful to quickly determine a treatment plan based on the shortest distance between the gross tumor volume (GTV) and organs at risk (OAR) measured using cone-beam computed tomography (CBCT) images.
Determining the distance between the tumor and the GI tract is essential to achieve dose constraints for OAR and to identify patients who may benefit from adapting the treatment plan. 14In this study, we focused on the shortest distance from the GTV to the GI tract and presumed that the daily GI tract dose could be predicted according to its distance.We aimed to investigate whether daily CT can predict the daily GI tract doses based on the shortest distance between the tumor and the GI tract.

Patients
This study was approved by the relevant institutional Ethics Review Committee (IRB number: 022-0193).All patients provided written informed consent for treatment.We retrospectively reviewed the records of patients treated with SBRT for pancreatic cancer between September 2020 and April 2023.Patients whose CT images were obtained prior to beam delivery on each treatment day, who underwent SBRT using intensitymodulated radiotherapy (IMRT), and who had a tumor located in the pancreatic head or body were included.Finally, the data of 12 patients who met these criteria were analyzed.Table 1 shows the patients' characteristics.
For respiratory-gated SBRT using a fiducial marker, a metallic embolization coil was implanted transarterially or gold anchors were implanted in the retroperitoneal region near the tumor in all patients.A dose was delivered when a marker was within ±2.0 mm of the planned coordinates relative to the isocenter (at natural expiration). 15SBRT was delivered with six mega-voltage (MV) beams with or without flattening filter-free by a TrueBeam (Varian Medical Systems), while implementing a SyncTraX FX4 (Shimadzu, Kyoto, Japan) for fiducial marker-based respiratory gating.At patient set-up, CBCT images were obtained and bone matching was performed using a six-dimensional couch.Translation-only registration was then performed based on the fiducial marker position.The protocol from marker implantation to SBRT was similar to that reported previously concerning lung or liver cancer. 16,17The SBRT plan was generated using step-andshoot IMRT of 7-10 portals and planned using Pinnacle 3 version 14.0 (Philips, Amsterdam, Netherlands) software.
Planning CT scan CT images were obtained after fasting for at least 6 h.Fourdimensional CT (4DCT) was performed using a real-time position management system (Varian Medical Systems, Palo Alto, CA, USA).The acquired 4DCT images were divided into 10 different three-dimensional (3D) CT images according to timebased sorting in 10 respiratory phases (0%, 10%, ..., 90%).Here, 0% CT implies CT performed at natural inspiration, while 50% CT implies CT performed at natural expiration.After the 4DCT scan, enhanced or non-enhanced planning CT was performed with a slice thickness of 2 mm at natural expiration as respiratory gating was carried out during this respiratory phase.During the planning CT scan, the CT images were examined to determine if they had been correctly obtained at natural expiration, which refers to the 50% phase of the 4DCT images.In this case, the 4DCT images were used only to confirm natural expiration and not used for the treatment planning.

SBRT planning
The treatment plan was generated on CT images at natural expiration, and available contrast-enhanced CT was registered against the planning CT for accurate delineation.The GTV was defined according to the available imaging data, including those obtained using diagnostic enhanced/non-enhanced CT, magnetic resonance imaging (MRI), and positron emission tomography.The clinical target volume (CTV) was generated as the GTV along with the tumor-vessel interface (TVI), which was defined as areas of major blood vessels within the GTV with a 5 mm margin. 18The planning target volume (PTV) was created through adding a 5 mm margin to the CTV.The planning at-risk volume (PRV) was generated through adding a 5 mm margin to each gastrointestinal organ, including the stomach, duodenum, small intestine, and large intestine (stomach_PRV, duodenum_ PRV, small intestine_PRV, and large intestine_PRV, respectively).These organs were contoured according to Radiation Therapy Oncology Group consensus guidelines. 19The modified PTV (PTV mod ) was defined as the PTV minus the area overlapping the

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Original research: Prediction of daily GI doses in SBRT for pancreatic cancer GI tract_PRV.The goal of the dose prescription was 40 Gy (100% of the prescribed dose) in five fractions for 90% of the PTV mod surrounded by 80-90% isodose lines. 18e OAR dose constraint for each PRV was the volume receiving 38 Gy (V 38 ) <0.5 cm 3 until January 2021 (patients 1-2) or V 33 <0.5 cm 3 (patients 3-12) thereafter.The other primary target goals and dose constraints are listed in Table 2.The initial SBRT plan was referred to as the reference plan (PLAN ref ).

Dose Evaluation
A non-contrast-enhanced CT (CT eval ) for daily dose evaluation was performed before each SBRT fraction under the same conditions as the treatment planning CT.These CT images were scanned with a treatment planning CT system following the same CT imaging conditions as the treatment planning CT scan in terms of CT equipment, parameters for CT imaging, vacuum cushion, body position, dietary restrictions, and respiratory status (natural expiration).For dose evaluation, the contours of the target and risk organs were generated as in the PLAN ref and were reviewed by at least two radiation oncologists.Here, the contours were manually created on the daily CT because the quality of the contours was not satisfactory in terms of deformable image registration, especially in the GI tract.The dose was recalculated on CT eval using the original beam data from the PLAN ref .
The recalculated plan for the daily dose evaluation was referred to as the PLAN eval .Prior to the daily dose evaluation, the 3D coordinates of the isocenter in the PLAN eval were determined based on the relationship between the 3D coordinates of the fiducial marker and those of the isocenter in the PLAN ref .
These methods are similar to those reported in previous studies regarding interfractional motion. 7Five fractions were evaluated for each of the 12 patients, resulting in 60 PLAN evals .

Data Analysis
To determine the locational relationship, the 3D shortest distance between the surface of the GTV and the GI tract was calculated using MIM Maestro software version 7.0 (MIM Software, Cleveland, OH, USA).In the exploratory data analysis, differences in the boundary between the stomach and the duodenum could potentially affect the calculated shortest distance from the GTV to the stomach or duodenum.In some cases, for example, a larger contour of the stomach may result in a shorter distance to the tumor, whereas a smaller contour may result in a longer distance to the tumor.These changes are due to differences in contours rather than interfractional motion of the GI tract.Therefore, the stomach and duodenum were evaluated together as the gastroduodenum. 20 aimed to determine whether the shortest distance between the GTV and the GI tract could predict the daily dose delivered to the GI tract.Therefore, we evaluated the association between daily changes in the shortest distance and daily doses.For dose evaluation, the D 0.5cc of PRV was extracted from the PLAN ref and PLAN eval .D Xcc was defined as the maximum dose delivered to a volume of X cc to the organ of interest.The dosimetric parameters and shortest distance were calculated using the following formulae to quantify the daily change: Since the dose constraints of the GI tract differed between patients, ratios were used for quantitative analysis of the daily dose changes (ΔD Xcc ).We examined the association between the Δshortest distance and the ΔD Xcc / PLAN ref , which represents the dose ratio of ΔD Xcc to D Xcc of the PLAN ref .
Spearman's correlation test was used in the statistical analysis to determine the association between the Δshortest distance and the ΔD Xcc / PLAN ref .
The paired differences were analyzed using paired Wilcoxon signed-rank tests, and categorical variables were analyzed using a chi-square test.For comparison of more than two groups, Kruskal-Wallis tests were used with post-hoc Dunn's tests.The coefficient of variation, calculated as the standard deviation (SD) divided by the mean, was also evaluated.A p-value < 0.05 was considered significant, and JMP Pro version 16.0 (SAS, Cary, NC) software was used to perform all statistical analyses.

Shortest Distance
In the PLAN ref and PLAN eval review, interfractional motion was observed even if the CT images were obtained at natural expiration and after fasting for at least 6 h (Figure 1).The median shortest distances between the GTV and the GI tract in the PLAN ref were 0 mm (IQR, 0-2.7) in the gastroduodenum, 16.7 mm (10.0-23.7) in the small intestine, and 16.7 mm (8.3-28.1) in the large intestine (Figure 2a).The distance was significantly smaller in the gastroduodenum than that in the small or large intestines (p < 0.001).The mean coefficients of variation ±SD in the shortest distance were 0.07 ± 0.34 in the gastroduodenum, 0.31 ± 0.20 in the small intestine, and 0.20 ± 0.13 in the large intestine.
The mean Δshortest distances with SD were 0.5 ± 1.7 mm in the gastroduodenum, 0 ± 8.0 mm in the small intestine, and 2.5 ±

DISCUSSION
This study investigated the dosimetric parameters of SBRT for pancreatic cancer in terms of the locational relationship between the tumor and GI tract.We quantified daily changes in the shortest distance from the GTV to the GI tract and their effect on daily GI tract doses.The distance was significantly shorter in the gastroduodenum than in the small or large intestine; therefore, the gastroduodenum would be more likely to receive high radiation doses.Spearman's correlation test results showed that daily GI tract doses could be predicted using the shortest distance in the small or large intestine, but not in the gastroduodenum, possibly due to its proximity to the GTV.Hence, dose recalculation is essential for predicting daily doses as determination of the gastroduodenal dose is needed to ensure safe delivery of SBRT for pancreatic cancer.
One challenge associated with SBRT is limiting GI tract doses to reduce the risk of late adverse events.Several studies have investigated the association between dosimetric parameters and late adverse events in the GI tract.In relation to the stomach, Feng et al proposed a normal tissue complication probability (NTCP) model to predict the risk of radiation-induced gastric bleeding. 21They reported that the highest dose was a critical predictor rather than the mean dose in the stomach.In relation to the duodenum, the maximum or D 1cc dose was reported to be more critical in predicting late toxicities. 22,23Based on these studies, the delivery of a high radiation dose to a small volume of the stomach or duodenum is closely associated with the occurrence of late adverse events; hence, dose reduction is necessary.In our study, D 0.5cc was used in the dose analysis as the institutional dose constraint was V 33 or V 38 < 0.5 cm 3 for PRV.In our study, we analyzed the stomach and the duodenum as one organ; therefore, no conclusions can be drawn for the stomach or duodenum separately.Nonetheless, the D 0.5cc dose was significantly higher in the gastroduodenum than that in the small or large intestine owing to its proximity to the GTV.The risk of developing late adverse events is likely to be higher in the gastroduodenum, as suggested in previous studies. 24,25garding the association between the Δshortest distance and ΔGI tract dose, a proportional dose-distance relationship was found in the small intestine and large intestine, but not in the gastroduodenum, probably due to differences in the shortest distance in each GI organ.In the sections of the GI tract located near the tumor, such as the gastroduodenum, The critical dose constraint in the GI tract was V 38 < 0.5 cm 3 (patients 1 and 2) or V 33 <0.5 cm 3 (patients 3-12).D 0.5cc refers to the maximum dose delivered to a volume of 0.5 cc in each organ.In contrast, non-highly optimized areas such as the small or large intestine have gentle and linear dose distribution curves.We found that the shortest distance in most of the PLAN eval was ≥6 mm in the small and large intestine.This background may explain the proportional association between the Δshortest distance and daily dose differences (ΔD 0.5cc / PLAN ref ) in the small and large intestine (Figure 3b).

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Original research: Prediction of daily GI doses in SBRT for pancreatic cancer being significantly higher in the stomach or duodenum but not in the bowel. 8Their study did not consider the distance between the GTV and OAR; however, daily dose uncertainties might be prominent in the stomach or duodenum.
Our study findings suggest that prediction of the daily dose in the gastroduodenum is difficult when based only on the shortest distance between the GTV and GI tract using daily CT images.
Our initial hypothesis was that a shorter distance would result in a higher D 0.5cc , while a longer distance would result in a lower D 0.5cc .As expected, the daily dose-distance relationship was proportional in relation to the small and large intestines.Contrastingly, the short distance between the gastroduodenum and GTV in pancreatic cancer may make it difficult to predict daily dose changes due to interfractional motion.Considering that 10 of 12 patients received the highest D 0.5cc in the gastroduodenum and that its dose is important to predict the risk of late adverse events in the GI tract, daily dose calculation is essential to ensure the safe delivery of treatment.
This study had several limitations.First, the shortest distance was generally based on contours used in clinical practice.At least two radiation oncologists approved these distances for clinical SBRT planning; however, the possibility of slight variations cannot be excluded.In particular, the shortest distance from the GTV to the GI tract was measured in millimeters.Therefore, the effect of possible contouring error may not have been negligible.Moreover, since the slice thickness of CT images used in this study was 2 mm, it was difficult to contour the target and risk organs from CT images with a slice thickness of ≤1 mm.Another limitation is the small number of samples.We only included 60 sets of daily CT images from 12 patients in our analysis, which means that definitive conclusions cannot be drawn from this study; hence, future studies are needed involving more patients.Because of this limitation in terms of the small number of study participants, those with different dose constraints were analyzed together.A steeper dose gradient between the target and OAR was observed in the V 33 <0.5 cm 3 group than in the V 38 <0.5 cm 3 group.However, the ΔD 0.5cc / PLAN ref of the gastroduodenum, which is the most important index in this study, did not differ significantly between patients with these two different dose constraints (p > 0.05).
In conclusion, the distance between the tumor and GI tract was smaller in the gastroduodenum than that in the small and large intestines.Prediction of the daily dose delivered to the small or large intestine may be possible based on the Δshortest distance using daily CT images; however, this method may be challenging to apply in the gastroduodenum.Recalculating the initial plan using daily CT images is essential to correctly evaluate the daily gastroduodenal dose.

FUNDING
This research is supported by the Japan Society for the Promotion of Science KAKENHI (grant number: 23K14857) and AMED under grant number JP22he2302001.

CONFLICT OF INTEREST
K.K. is an employee of the research institute of Hitachi, Ltd., currently working at Hokkaido University, under a secondary agreement.K.K. declares that this research has no relationship with Hitachi, Ltd.All other authors declare that they have no conflicts of interest.

Figure 1 .
Figure 1.A case showing interfractional motion The gross tumor volume (red) and gastroduodenum (pink) are shown on each CT image.The shape of the gastrointestinal tract is different due to the interfractional motion, leading to daily changes in the shortest distance between the tumor and gastrointestinal tract.CT, computed tomography.

Figure 2 .
Figure 2. (a) The shortest distance from the GTV to the GI tract in the PLAN ref and (b) daily changes in the shortest distance in each patient.(a) * indicates a significance between the two groups using Dunn's test.(b) The change in the shortest distance to the gastroduodenum in patients 6, 7, 9-12 is zero, which means the GTV and gastroduodenum are always adjacent to each other in the planning CT and daily CT images.GI tract, gastrointestinal tract; GTV, gross tumor volume; NS, not significant.

a
For patient No.12, considering the dose to the tumor, the gastroduodenal dose in the PLAN ref was deemed clinically acceptable.6 of 8 birpublications.org/bjroBJR Open;5:20230043BJR|OpenUchinami et al an SBRT plan is highly optimized using steep dose distribution curves to ensure adherence to the dose constraints of the GI tract.However, the PLAN eval involved dose distribution obtained by recalculating the original beam data of the PLAN ref , which indicated that the PLAN eval was not precisely optimized based on daily CT images.The shortest distance between the gastroduodenum and the GTV in the PLAN eval was ≤6 mm in all patients (100%).Therefore, a slight positional change due to interfractional motion can lead to dose uncertainty in terms of predictability in the PLAN eval .

Figure 3 .
Figure 3. (a) The ΔD 0.5cc / PLAN ref in each patient and the (b) association between the Δshortest distance and ΔD 0.5cc / PLAN ref .(a) ΔD 0.5cc / PLAN ref indicates the ratio of ΔD 0.5cc dose to D 0.5cc dose in PLAN ref for quantitative analysis (b) The horizontal axis shows the Δshortest distance, while the vertical axis shows the ΔD 0.5cc / PLAN ref of PRV.The single dot indicates the evaluation of one fraction (PLAN eval ) in a case.As 12 patients were treated with radiotherapy delivered in five fractions, each panel contains a total of 60 dots.The (r) in each panel indicates the Spearman's correlation coefficients.GI tract_PRV, planning at-risk volume of the gastrointestinal tract; GTV, gross tumor volume.

Table 2 .
General dose constraints for SBRT GI tract, gastrointestinal tract; GTV, gross tumor volume; PRV, planning at risk volume; PTV mod , planning target volume for evaluation; SBRT, stereotactic body radiation therapy.V X refers to volumes receiving X Gy at least; D X% refers to the dose received by X percent of the target volume at least BJR Open;5:20230043

Table 3 .
D 0.5cc (Gy) at PLAN ref PLAN ref , the initial stereotactic body radiation therapy reference plan; PRV, planning at risk volume.

Table 4 .
Spearman's correlation test between the Δshortest distance and the daily dose CC, correlation coefficients; PLAN ref , reference plan of stereotactic body radiotherapy for pancreatic cancer; PRV, planning at risk volume.ΔD Xcc /PLAN ref means the ratio of ΔD Xcc dose to D Xcc dose in PLAN ref 7 of 8 birpublications.org/bjroBJR Open;5:20230043